Citations

INTRODUCTION: The recent US Food and Drug Administration approval of resmetirom for treating metabolic dysfunction-associated steatohepatitis in patients necessitates patient selection for significant fibrosis or higher (≥F2). No existing vibration-controlled transient elastography (VCTE) algorithm targets ≥F2. METHODS: The mAchine Learning ADvanceD fibrosis and rIsk metabolic dysfunction-associated steatohepatitis Novel predictor (ALADDIN) study addressed this gap by introducing a machine-learning-based web calculator that estimates the likelihood of significant fibrosis using routine laboratory parameters with and without VCTE. Our study included a training set of 827 patients, a testing set of 504 patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease from 6 centers, and an external validation set of 1,299 patients from 9 centers. Five algorithms were compared using area under the curve (AUC) in the test set: ElasticNet, random forest, gradient boosting machines, XGBoost, and neural networks. The top 3 (random forest, gradient boosting machines, and XGBoost) formed an ensemble model. RESULTS: In the external validation set, the ALADDIN-F2-VCTE model, using routine laboratory parameters with VCTE (AUC 0.791, 95% confidence interval [CI]: 0.764–0.819), outperformed VCTE alone (0.745, 95% CI 0.717–0.772, P < 0.0001), FibroScan-aspartate aminotransferase (0.710, 0.679–0.748, P < 0.0001), and Agile-3 model (0.740, 0.710–0.770, P < 0.0001) regarding the AUC, decision curve analysis, and calibration. The ALADDIN-F2-Lab model, using routine laboratory parameters without VCTE, achieved an AUC of 0.706 (95% CI: 0.668–0.749) and outperformed Fibrosis-4, steatosis-associated fibrosis estimator, and LiverRisk scores. DISCUSSION: Along with the steatosis-associated fibrosis estimator model developed to target significant fibrosis or higher, ALADDIN-F2-VCTE (https://aihepatology.shinyapps.io/ALADDIN1) uniquely supports a refined noninvasive approach to patient selection for resmetirom without the need for liver biopsy. In addition, ALADDIN-F2-Lab (https://aihepatology.shinyapps.io/ALADDIN2) offers an effective alternative when VCTE is unavailable.

ABSTRACTImmune thrombotic thrombocytopenic purpura (iTTP) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular occlusion secondary to acquired ADAMTS13 deficiency. Contemporary data regarding iTTP treatment practices in the US, including the use of caplacizumab, are lacking. We aimed to characterize the demographics and therapies, including medications and apheresis practices, in patients with iTTP in the US. We retrospectively analyzed iTTP cases at 15 sites in the US that provide comprehensive care for patients with iTTP. The time‐period assessed was from January 1, 2017 to December 31, 2021. Our primary objective was to analyze data by iTTP episode, inclusive of initial episodes and relapses. A total of 390 iTTP episodes were reported for 280 unique individuals (187 females, 93 males). Thirty‐day mortality was 3.7% (14/374), and 6‐month mortality was 7.4% (27/367). TPE details were reported for 343 episodes, among which 261 underwent at least one procedure (median 6, IQR 3–11). Among the 261 episodes with at least one therapeutic plasma exchange (TPE) performed, 82.0% (214/261) used only plasma. Caplacizumab was used either alone or in combination with other agents in 43 (11.0%) episodes. Management strategies for iTTP remain varied across centers in the US, with a variety of combinations for TPE replacement fluids and therapeutic agents, as well as limited use of caplacizumab. Further research and standardization of treatment regimens may further reduce mortality in this condition.

Importance Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. Objective To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). Design, Setting, and Participants This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2 -positive (formerly HER2 -positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Intervention Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. Main Outcome Measures The primary outcome was ipsilateral breast tumor recurrence. Results Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2 -positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. Conclusions and Relevance The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02945579

AbstractDespite the pivotal role of communication skills in genetic counseling, communication strategies employed by genetic counselors in their current practice remain largely unexplored. The field of genetic counseling could benefit from updated simulated genetic counseling sessions conducted by genetic counselors illustrating a diversity of skills. This paper outlines the development and evaluation of updated simulations used to develop an online training course to identify genetic counseling skills and to assess how commonly these skills are used. Practicing genetic counselors in the United States were recruited to counsel trained standardized patients across six pretest and posttest simulated sessions in cancer, prenatal, and cardiology genetics settings. Sessions were coded using the novel Genetic Counseling Skills Checklist to identify which communication and counseling skills were utilized. Standardized patients were asked to provide session quality ratings and written feedback, which were analyzed using descriptive statistics and content analysis, respectively. Results from 64 recorded sessions involving 20 counselors from a variety of training programs, racial and ethnic backgrounds, states of residence, and with varying years of clinical experience revealed utilization of a broad array of skills across specialty types and clinical indications. The total number of unique skills used varied widely from 12 to 49, with an average of 35.8 out of 56 possible skills checked per session. Differences in skill usage were observed between pretest and posttest sessions. Standardized patient comments were predominantly positive with a focus on information delivery and empathetic responses. Perceptions of areas of improvement were giving less information, having clearer delivery, and expressing more empathy. This work led to the creation of a training course showcasing various skills used by practicing genetic counselors, which summarizes commonly used skills and other promising but less frequently utilized ones.

Abstract Background The treatment of locally advanced rectal cancer now includes “watch-and-wait” (WW) management for patients who exhibit a clinical complete response (cCR) to total neoadjuvant therapy (TNT). We assessed patients’ knowledge and preferences regarding WW with the goal of incorporating patient input into clinical trial design. Methods Rectal cancer patients in advocacy groups (COLONTOWN/Rectalburgh and Fight CRC) were surveyed regarding perceptions about treatment strategies, tolerable risks of treatment failure, and preferences on clinical trial design. Surveys were initially distributed in 2019, with the shift toward WW prompting re-survey of select questions in 2023. Results All respondents preferred enrollment in trials that incorporated patient input. Most respondents (76%) preferred treatment that incorporated chemotherapy escalation over radiation escalation. Furthermore, when presented with a hypothetical patient who developed a cCR after chemoradiation (without the option for WW), 58% of patients chose surgical treatment (with 100% risk of permanent ostomy and 80% chance of cure) over omission of surgery (with &lt;80% chance of cure). In contrast, when the hypothetical patient developed a cCR after TNT (with an option for WW), 82% of patients opted for selective WW over surgery. Conclusions This work successfully integrated patient advocacy groups as a resource for obtaining patient input. Surveys revealed patients had a strong preference for chemotherapy escalation, for selective WW when offered, and for incorporation of input into future clinical trial design. These findings describe how well-informed patients approach complex medical decision-making and serve as a starting point for future studies seeking to incorporate patient voices.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models’ performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P &lt; .0001) and worse OS (HR, 2.09; P &lt; .0001). Bootstrap bias–corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P &lt; 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44–0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.